Since oxygen is essential for bleomycin-induced DNA scission to occur in vitro, possibly mediated by superoxide and hydroxyl free radicals, the role of oxygen will be studied in cell culture, and in a mouse model of lung toxicity. Some antineoplastic drugs used in combination with bleomycin may potentiate its pulmonary toxicity, and these deleterious drug interactions may be identified by combination toxicity studies in the mouse model. Potentially beneficial interactions with antioxidants, inhibitors of collagen synthesis, or anti-inflammatory agents will also be investigated. Bleomycin hydrolase activity will be measured in several murine tumors, in human cancer surgical specimens, and in lung tissues when available. The importance of bleomycin metabolism in determining tumor sensitivity and toxicity will be examined. Ultimately, this may enable us to predict responsiveness to bleomycin therapy in individual patients, and lead to methods for identifying patients at greater risk for developing pulmonary toxicity. These studies should enhance our understanding of the mechanisms of activity of bleomycin, and lead to more rational use of this drug.